Process of producing nu-acetyl methionine



United States Patent PROCESS OF PRODUCING N-ACETYL METHIONINE John P. Calianan, Pasadena, and Abner P. Patton, Glen Burnie, Md., assignors to National Distillers Products Corporation, New York, N. Y., a corporation of Virgmia No Drawing. Application February 2, 1953, Serial No. 334,716

i 8 Claims. or. 260-534) NH; (methionine) (acetic anhydride) H N C H3 C O O H i) CH: O

(N-acetyl methionine) (acetic acid) N-acetyl methionine is of particular utility in those fields requiring the use of methionine as a therapeutic agent because of its increased solubility in water. The sodium salt of N-acetyl methionine is extremely soluble in water and its pH characteristic is close to the neutral point.

It has previously been proposed to acetylate methionine by reacting acetic anhydride with the methionine dissolved in glacial acetic acid. It has also been proposed to acetylate the sodium salt of methionine in aqueous solution by reaction with acetic anhydride or ketene.

However, previous methods proposed for the acetylation of methionine have been subject to certain disadvantages which have detracted from their commercial use. For instance, where the acetylation is carried out in glacial acetic acid, it is necessary that the latter be removed by distillation, preferably under reduced pressure, before the N-acetyl methionine can be isolated. When the acetylation is carried out in aqueous alkaline solution, it is essential that substantially all the water be removed before the N-acetyl methionine can be separated by crystallization. This latter method also requires acidification of the reaction mixture since the sodium salt is so soluble in water that its crystallization therefrom is exceedingly difiicult. If the water is not removed from the aqueous reaction mixture by distillation, one must resort to solvent extraction with its attendant difiiculties and relatively low recovery.

It will be understood that reference herein and in the appended claims to methionine is intended to mean the ordinary dlmethionine commercially available.

It is an object of my present invention to provide a simple method of producing N-acetyl methionine whereby the previously experienced difficulties are avoided and the desired product can be obtained directly by crystallization from the reaction mixture. A further object is to obtain directly from the reaction mixture a product of commercial purity and particularly low in N-acetyl EQQ methionylmethionine, a by-product normally found in l -acetyl methionine in substantial amounts, particularly where the acetylation is carried out under anhydrous conditions.

These and other advantages, as will hereinafter appear, are obtained by my present process, in accordance with which methionine is reacted with acetic anhydride in the presence of an organic liquid reaction medium which is inert with respect to the acetic anhydride, methionine and N-acetyl methionine and which is a solvent for the N-acetyl methionine at the reaction temperature. Following the reaction, the mixture is cooled and the N-acetyl methionine is thereby crystallized directly from the reaction mixture in a surprisingly high state of purity.

As appears from the foregoing equation, the acetic anhydride and methionine react mol for mol. However, it is generally advantageous to use a proportion of the acetic anhydride slightly in excess of that theoretically required, in order to force the reaction more nearly to completion.

Organic liquids suitable for use as the reaction medium, must necessarily be inert with respect to acetic anhydride in order that there be no contamination of the desired product with other acetylation products and it must be a solvent for the N-acetyl methionine and preferably have good solvent action therefor at the temperature of the reaction and greatly reduced solubility therefor at lower temperatures. The reaction medium should also be inert with respect to the methionine and N-acetyl methionine. Advantageously, the medium should have little or no solvent action on the methionine, but preferably is a solvent for the acetic anhydride.

For this purpose, We have, with advantage, used lower alkyl acetates or ketones. For instance, ethyl acetate (99% purity) and acetone have been found to be particularly eficacious. O her similar esters and ketones which may be used, with advantage, include methyl acetate, npropyl acetate, isopropyl acetate, butyl acetate, methyl ethyl ketone, and diethyl ketone. The inert liquid used should have a boiling point not greatly exceeding 100 C. and more advantageously between about 55 C. and 90 C.

Since methionine is relatively insoluble in useful reaction media, it is, with advantage, introduced in a finely divided form so as to offer an increased amount of surface to the acetic anhydride and thus expedite the reaction. It has been found that a particle size of (A. S. T. M.) mesh or finer is most advantageous. When larger sized particles, or lumps of methionine, are used, there is a tendency toward the formation of increased amounts of N-acetyl methionylmethionine, probably due to the longer reaction time required. The finely divided methionine is, with advantage, mixed with the organic reaction medium to form a slurry prior to the adition of the acetic anhydride.

The acetylation of methionine is an exothermic reaction and the heat evolved may be conventionally dissipated by allowing the reaction medium to boil and condensing and returning the condensed vapors to the reaction mixture. When a higher boiling reaction medium is used, the boiling point, and thus the reaction temperature, may be lowered by decreasing the pressure on the reaction system. Conversely, when a reaction medium is used having a boiling point so low that the reaction rate is too slow for commercial purposes, the temperature of the reaction mixture may be increased by increasing the total pressure on the reactionsystem.

By proper choice of reaction medium and by adjusting the pressure on the reaction system, the reaction tempera-. ture may be varied over a considerable range. I have found, however, that, in order to minimize the formation of N-acetyl methionylmethionine, the reaction temperature should not greatly exceed 100 C. Reaction temperatures of about 80 to C. have been found to give adequate speed of reaction -for commercialpurposes with a minimum of undesirable by-product formation and, therefore, have been found to be particularly advantageous. Lower reaction temperatures are generally undesira'bie because of decreased reaction rate, but are otherpurity of the crystalline N-acetyl methionine separated from the reaction mixture, at the indicated temperatures, are illustrated by the data set' forth in the table below. In each of these operations, the amount of acetic anhydride used was 9% in excess of the theoretical requirement, the

Wise acceptable. It is generally undesirable to carry out methionine was of a fineness equivalent to 80 mesh and the reaction at temperatures below about room tempera- 1.3 parts of the reaction medium was used per part of ture. methionine by weight. The reaction temperature was ap-. The ratio of the inert reaction medium to methionine proximately 80 C. in those operations where ethyl ace is not particularly critical. Excellent results have been obtate was used as the reaction medium and approximately tained where about 1.5 parts to 2.5 parts of inert medium 65 C. where acetone was used as the reaction medium.

TABLE A Cid Percent purity of N-ag itg lduethioninc crystallizing Reaction Percent; Medium Water L Kind Percent -10 4% -2 0 2 3 ethyl acetate. 0.0 nzsot 0.0

Do -i 3.0 HzSOi 0.0 07.2-09.0 3v 0 Hzsol 0. 2 0e. 7

3.0 E2504 0.5 98.3-99.0 7.0 H2804 0.8 98.3-99.0 15.0 HHSO; 0.8 97.2-07.7 3.0 HBPO; 0.8 09.3 3.0 HS'PO; 0. s

per part of methionine, by Weight, were used. Still great- The invention will be further illustrated by the follower proportions of solvent may be used but will result in ing specific examples: a decreased amount of crystallized, N-acetyl methionine Example I Pe a frag? t reactlon mixture on cooling as Wm 150 grams of methionine, of about 80 mesh particle be Pr eSe nt1y deS?nbed' size, and 250 cc. of ethyl acetate of 99% purity were fi qn P d the i' F ff placed in a 1 liter glass flask, equipped with a stirrer, redissolved n the mert reaction medium as formed is flux condenser, thermometerI dropping funnel and heating crysLalbhzed therefrom by coohng.th.e reactlon medmm mantle. This mixture was agitated and the agitation conadvailagwusly. a temPeramfe Wlthm the range of i tinned throughout the reaction period. A solution of l T 20 crystinlzatlon temperaturesuwlthm gram of concentrated sulfuric acid in 5 grams of water th a g 0t to 15 have been used with B was added and thereafter 108 grams of acetic anhydride i f e f As h tefhperature of the fi was added and the mixture slowly heated to the boiling 9. i lowered Solublhty of the point of the mixture, about 80 C. Heating was continlonm? dicreasf: Wlth th resultant separanon of t e 40 tied with refluxing until a clear solution resulted, this reproducftherelwmmFfYStanme form V quiring about 20 minutes. The reaction mixture was As F Z Fi ethyl acetate arld 9 h then transferred to a beaker and cooled to 5 C. which been used with part cular advantage as a reaction mediumi resulted in crystallization of the N acetyl methionine They ha ve been found to be good solvents for li gh formed by the reaction. The mixture was then filtered meth onin at h fh h and to have through a Buchner funnel to separate the crystals and the solven Power for l h Hydrocarbons e separated crystals were Washed with cold ethyl acetate q' range am also Wlth respec? to acetlc an 1 and then dried in a vacuum drier at a temperature of about tinge. have nly sllg solvfant acftlon f 80 C. There was obtained by this reaction 150 grams 2233 and therefore less use 111 as t e reacnon of dry, white granular crystals having a melting point of C a While the reaction will proceed under conditions Pre- 5 Conslstmg of N acetyl methlomne of a viously described in the absence of any water or inorgan- Emm l H ic acid, We have found it particularly advantageous to p e carry out the reaction in the presence of small controlled The Pompohehts and Proportions thefeOf used in EX- amounts of water and an inorganic acid. In the absence ample x p that 250 of acetone was Used in Place of water and inorganic acid, completion of the acetylation 55 of the ethyl acetate: were Placed ill the flask, agitated and is more diflicult and, under such conditions, increased heated to the b0ih11g Point, as described ill the Preceding amounts of the by-product N-acetyl methionylmethionine example- In this Operation, the boiling Point Of the ITliX- have been Obtained ture was about C. and the refluxing was continued for For best results, water should be present in the reaction pp a y 1 1101111 he mixture Was then cooled to mixture in an amount within the range of about 0.4% to 60 C. and filtered, the crystals thus recovered being washed 7.0%, based on the weight of methionine. If substantialh cold acetone and dried- This Operation resulted in ly more than about 7.0% ofwater is present, a loss of 139 grams of cfyhallhle y methionine having a acetic anhydride is experienced due to its hydrolysis to mhhihg P0311t of and a P y of 985%- acetic acid. Especially good results have been obtained where 3.0% water, based on the weight of methionine, Example has been used. 7 150 pounds of methionine, of a particle size approxi- As the inorganic acid present during the reaction, any mately 80 mesh, and 220 pounds of ethyl acetate were strong inorganic acid may be used, but sulfuric acid and mixed in a 150 gallon vessel, equipped with an agitator, a phosphoric acid have been used with particular a'dvansteam jacket, an inlet connection and a reflux condenser. tage. For best results; the amount of such inorganic acid The mixture was agitated to form a slurry and the agitapresent should be within the range of 0.1% to 0.7%, tion was continued throughout the reaction. To this slurry based on the weight of methionine used. Particularly there was added a solution of 0.5 pound concentrated good results have been obtained using about 0.5% acid. sulfuric acid and 5 pounds of water. There was then The efiect of varying the amountof water, the amount added 108 pounds of acetic anhydride and the temperaand kind of acid and-the reaction medium used upon the ture of the mixture was raised to the boiling point of the mixture and this temperature maintained with refluxing until a clear solution resulted. The reaction mixture was then transferred to a crystaii ler, cooled to 5 C. and filtered to separate the resultant crystals. These crystals were then washed with cold ethyl acetate and dried under a vacuum at a temperature of about 80 C. By this operation, there was obtained 150 pounds of N-acetyl methionine crystals having a melting point of 113-1 15 C. and a purity of 98.5%.

We claim:

1. Method of producing N-acetyl methionine which comprises reacting acetic anhydride with methionine at an elevated temperature not exceeding about 100 C. in an organic liquid reaction medium inert with respect to e acetic anhydride and boiling within the range of about 55 C.-100 C., said medium being a solvent for the N-acetyl methionine at the reaction temperature, and thereafter cooling the reaction mixture and thereby crystallizing the N-acetyl methionine from the solution.

2. The method of claim 1 in which the reaction medium is selected from the group consisting of the lowed alkyl acetates and ketones.

3. The process of claim 2 in which the reaction medium is ethyl acetate.

4. The process of claim 2 in which the reaction medium is acetone.

5. The process of claim 1 in which the reaction medium is one having a boiling point within the range of to 90 C.

6. The process of claim 1 in which the reaction is carried out in the presence of water in an amount within the range of 0.4% to 7% and a small amount of a strong inorganic acid within the range of 0.1% to 0.7%, each based on the weight of methionine.

7. The process of claim 1 in which the methionine is introduced as a slurry of finely divided methionine of a particle size not exceeding mesh.

8. The process of claim 1 in which the reaction is carried out at a temperature within the range of 80 to C.

OTHER REFERENCES MacArdle: Solvents in Synthetic Org. Chem. (van Nostrand), pgs. 1-3, 7-11, 13-17 (1925). 

1. METHOD OF PRODUCING N-ACETYL METHIONINE WHICH COMPRISES REACTING ACETIC ANHYDRIDE WITH METHIONINE AT AN ELEVATED TEMPERATURE NOT EXCEEDING ABOUT 100* C. IN AN ORGANIC LIQUID REACTION MEDIUM INERT WITH RESPECT TO ACETIC ANHYDRIDE AND BOILING WITHIN THE RANGE OF ABOUT 55* C.-100* C., SAID MEDIUM BEING A SOLVENT FOR THE N-ACETYL METHIONINE AT THE REACTION TEMPERATURE, AND THEREAFTER COOLING THE REACTION MIXTURE AND THEREBY CRYSTALLIZING THE N-ACETYL METHIONINE FROM THE SOLUTION. 